Identifying the research priorities for schema therapy : A Delphi consensus study

Despite the popularity of schema therapy, there exist several important gaps in research on the schema therapy model and its effectiveness. The number of gaps makes it difficult to determine the research areas of the highest strategic priority to advance schema therapy. The objective of this study was to establish consensus among schema therapy clinicians and researchers on the priority areas for future schema therapy research. A panel of experts in schema therapy (43 clinicians and 13 researchers) participated in a Delphi consensus study. The research areas rated were developed by interviewing the founder of schema therapy, Jeffrey Young, conducting a focus group with the executive board of the International Society for Schema Therapy and screening recent reviews on schema therapy for recommendations for future research. The panel rated 81 research areas in terms of priority across three rounds. Nineteen research areas were rated by 75% of the panel as ‘Very high priority’ or ‘High priority’. These priorities reflected four broad themes: (1) schema therapy constructs and measures, (2) the theoretical assumptions underlying schema therapy, (3) schema therapy and theory in relation to different contexts and outcomes and (4) schema therapy effectiveness and mechanisms of change. The findings are important for establishing a clear research agenda for the future of schema therapy

The influence of copper (II) ions on the structure and stability of the prion protein and its interaction with the amyloid-beta peptides.

PhDThe prion protein (PrPC) is a cell surface glycoprotein that binds Cu2+ ions. The misfolding and oligomerisation of PrPC is responsible for a range of transmissible spongiform encephalopathies (TSEs) in mammals. As changes in PrPC conformation are intimately linked with disease pathogenesis, the effect of Cu2+ ions on the structure and stability of PrPC has been investigated. In chapter 3, urea unfolding studies indicate that Cu2+ ions destabilise the native fold of PrPC. The mid-point of the unfolding transition is reduced by 0.73 ± 0.05 M urea in the presence of Cu2+ ions equating to an appreciable difference in free energy of unfolding (∆∆GU[D]50%), 2.02 ± 0.05 kJmol-1. This suggests that in Prion diseases, Cu2+ ions could destabilise the native fold of PrPC and make the transition to a misfolded state more favourable. Furthermore, Cu2+ induced changes in secondary structure observed for small fragments of the protein are related to the full-length prion protein. An increase in -sheet like character is observed when Cu2+ ions are present, this is due to local Cu2+ ion coordination to the individual binding sites of the amyloidgenic region. Cu2+ induced changes in the secondary structure of the N-terminal domain, PrP(23-126) and full-length PrP(23-231), are attributed to Cu2+ ions binding within the octarepeat region of PrPC. Oxidative stress is also a well-recognised feature of Prion diseases. In chapter 4, the effects of Cu2+ catalysed oxidation of PrP on the structure and stability are discussed. 2D 1H-15N HSQC NMR studies of PrPC indicate that specific key residues are perturbed upon methionine (Met) oxidation by H2O2. These residues are involved in the hydrophobic packing of the structured core of the protein, stabilising its ternary structure. Urea unfolding studies indicate that the oxidation of PrPC by H2O2 and to a greater extent Cu2+ ions with peroxide significantly reduce the thermodynamic stability of PrPC. Cu2+ catalysed oxidation of PrP causes much more significant alteration of the structure. 2D 1H-15N HSQC NMR spectroscopy indicates that the structured C-terminal portion of PrP becomes a large molten-globule, made of monomeric species. FT-IR and far-UV-CD spectroscopy indicate that this molten-globule is rich in β-sheet. These observations supports a hypothesis that oxidation of PrP destabilises the native fold of PrPC, making the transition to PrPSc more energetically favourable. This study gives a structural and thermodynamic explanation for the high levels of oxidised Met residues in scrapie isolates. Finally, in chapter 5 the interaction of PrPC with Aβ peptide, responsible for Alzheimer’s disease (AD), is investigated. In particular, the influence of full length PrP and fragments on the kinetics of Aβ fibril growth is investigated. The complete inhibition Aβ fibril formation is observed when as little as one-twentieth of the molar ratio of PrPC is used. The unstructured N-terminus of PrPC, residues 23 to115, is thought to be crucial for this inhibition, while, residues 116 to 231 have no influence on the fibril formation. Gel filtration chromatography indicates that the complex formed by PrPC with an Aβ oligomer is 12 to 24 monomers in size.Biotechnology and Biological Sciences Research Counci

On the Thermodynamics and Experimental Control of Twinning in Metal Nanocrystals

International audienceThis work demonstrates a new strategy for controlling the evolution of twin defects in metal nanocrystals by simply following thermodynamic principles. With Ag nanocrystals supported on amorphous SiO2 as a typical example, we establish that twin defects can be rationally generated by equilibrating nanoparticles of different sizes through heating and then cooling. We validate that Ag nanocrystals with icosahedral, decahedral, and single‐crystal structures are favored at sizes below 7 nm, between 7 and 11 nm, and greater than 11 nm, respectively. This trend is then rationalized by computational studies based on density functional theory and molecular dynamics, which show that the excess free energy for the three equilibrium structures correlate strongly with particle size. This work not only highlights the importance of thermodynamic control but also adds another synthetic method to the ever‐expanding toolbox used for generating metal nanocrystals with desired properties.

Decay of Correlations in a Topological Glass

In this paper we continue the study of a topological glassy system. The state space of the model is given by all triangulations of a sphere with $N$ nodes, half of which are red and half are blue. Red nodes want to have 5 neighbors while blue ones want 7. Energies of nodes with other numbers of neighbors are supposed to be positive. The dynamics is that of flipping the diagonal between two adjacent triangles, with a temperature dependent probability. We consider the system at very low temperatures. We concentrate on several new aspects of this model: Starting from a detailed description of the stationary state, we conclude that pairs of defects (nodes with the "wrong" degree) move with very high mobility along 1-dimensional paths. As they wander around, they encounter single defects, which they then move "sideways" with a geometrically defined probability. This induces a diffusive motion of the single defects. If they meet, they annihilate, lowering the energy of the system. We both estimate the decay of energy to equilibrium, as well as the correlations. In particular, we find a decay like $t^{-0.4}$

Bioactivity and structural properties of chimeric analogs of the starfish SALMFamide neuropeptides S1 and S2

The starfish SALMFamide neuropeptides S1 (GFNSALMFamide) and S2 (SGPYSFNSGLTFamide) are the prototypical members of a family of neuropeptides that act as muscle relaxants in echinoderms. Comparison of the bioactivity of S1 and S2 as muscle relaxants has revealed that S2 is ten times more potent than S1. Here we investigated a structural basis for this difference in potency by comparing the bioactivity and solution conformations (using NMR and CD spectroscopy) of S1 and S2 with three chimeric analogs of these peptides. A peptide comprising S1 with the addition of S2's N-terminal tetrapeptide (Long S1 or LS1; SGPYGFNSALMFamide) was not significantly different to S1 in its bioactivity and did not exhibit concentration-dependent structuring seen with S2. An analog of S1with its penultimate residue substituted from S2 (S1(T); GFNSALTFamide) exhibited S1-like bioactivity and structure. However, an analog of S2 with its penultimate residue substituted from S1 (S2(M); SGPYSFNSGLMFamide) exhibited loss of S2-type bioactivity and structural properties. Collectively, our data indicate that the C-terminal regions of S1 and S2 are the key determinants of their differing bioactivity. However, the N-terminal region of S2 may influence its bioactivity by conferring structural stability in solution. Thus, analysis of chimeric SALMFamides has revealed how neuropeptide bioactivity is determined by a complex interplay of sequence and conformation

Structural analysis of the starfish SALMFamide neuropeptides S1 and S2: The N-terminal region of S2 facilitates self-association

The neuropeptides S1 (GFNSALMFamide) and S2 (SGPYSFNSGLTFamide), which share sequence similarity, were discovered in the starfish Asterias rubens and are prototypical members of the SALMFamide family of neuropeptides in echinoderms. SALMFamide neuropeptides act as muscle relaxants and both S1 and S2 cause relaxation of cardiac stomach and tube foot preparations in vitro but S2 is an order of magnitude more potent than S1. Here we investigated a structural basis for this difference in potency using spectroscopic techniques. Circular dichroism spectroscopy showed that S1 does not have a defined structure in aqueous solution and this was supported by 2D nuclear magnetic resonance experiments. In contrast, we found that S2 has a well-defined conformation in aqueous solution. However, the conformation of S2 was concentration dependent, with increasing concentration inducing a transition from an unstructured to a structured conformation. Interestingly, this property of S2 was not observed in an N-terminally truncated analogue of S2 (short S2 or SS2; SFNSGLTFamide). Collectively, the data obtained indicate that the N-terminal region of S2 facilitates peptide self-association at high concentrations, which may have relevance to the biosynthesis and/or bioactivity of S2 in vivo

ValueGuard: Protection of Native Applications against Data-Only Buffer Overflows

Code injection attacks that target the control-data of an application have been prevalent amongst exploit writers for over 20 years. Today however, these attacks are getting increasingly harder for attackers to successfully exploit due to numerous countermeasures that are deployed by modern operating systems. We believe that this fact will drive exploit writers away from classic control-data attacks and towards data-only attacks. In data-only attacks, the attacker changes key data structures that are used by the program’s logic and thus forces the control flow into existing parts of the program that would be otherwise unreachable, e.g. overflowing into a boolean variable that states whether the current user is an administrator or not and setting it to “true” thereby gaining access to the administrative functions of the program. In this paper we present ValueGuard, a canary-based defense mechanism to protect applications against data-only buffer overflow attacks. ValueGuard inserts canary values in front of all variables and verifies their integrity whenever these variables are used. In this way, if a buffer overflow has occurred that changed the contents of a variable, ValueGuard will detect it since the variable’s canary will have also been changed. The countermeasure itself can be used either as a testing tool for applications before their final deployment or it can be applied selectively to legacy or high-risk parts of programs that we want to protect at run-time, without incurring extra time-penalties to the rest of the applications.status: publishe

Causes and risk factors for common mental illnesses : the beliefs of paediatric hospital staff in the United Arab Emirates

Background Children and adolescents with chronic physical health conditions are vulnerable to poor mental health outcomes. The measurement of mental health literacy of health professionals working with such populations is important because of their role in promoting early and appropriate help-seeking. This study sought to determine the beliefs regarding the causes of and risks factors for three types of mental illnesses amongst health professionals in United Arab Emirates. Method A culturally validated mental health literacy survey presenting three vignettes of fictional characters meeting diagnostic criteria for posttraumatic stress disorder, depression with suicidal thoughts and psychosis was distributed. The survey measured health care professionals’ beliefs regarding the causes of and risk factors for these disorders. Results A total of 317 health care professional (> 90% nurses) were surveyed from across the UAE. Although 43.8% correctly endorsed exposure to a ‘traumatic event’ as the most likely cause for developing posttraumatic stress disorder, there was a more limited understanding of the contribution of biopsychosocial factors to the development of the mental illness, particularly for psychosis. Participant socio-demographic variables were associated with attributions of religious or spiritual beliefs and personal weakness as causal and/or vulnerability factors in the development of depression with suicidal thoughts and psychosis. Conclusions Efforts to improve mental health systems and health care providers in UAE and other similar Middle Eastern countries requires targeted mental health literacy programs that seek to integrate biopsychosocial models of mental illness and their treatment with the positive aspects of religious and cultural beliefs that are dominant in this region

Outdoor Air Pollution Exposure and Inter-relation of Global Cognitive Performance and Emotional Distress in Older Women

The interrelationships among long-term ambient air pollution exposure, emotional distress and cognitive decline in older adulthood remain unclear. Long-term exposure may impact cognitive performance and subsequently impact emotional health. Conversely, exposure may initially be associated with emotional distress followed by declines in cognitive performance. Here we tested the inter-relationship between global cognitive ability, emotional distress, and exposure to PM2.5 (particulate matter with aerodynamic diameter 2 (nitrogen dioxide) in 6118 older women (aged 70.6 ± 3.8 years) from the Women’s Health Initiative Memory Study. Annual exposure to PM2.5 (interquartile range [IQR] = 3.37 μg/m3) and NO2 (IQR = 9.00 ppb) was estimated at the participant’s residence using regionalized national universal kriging models and averaged over the 3-year period before the baseline assessment. Using structural equation mediation models, a latent factor capturing emotional distress was constructed using item-level data from the 6-item Center for Epidemiological Studies Depression Scale and the Short Form Health Survey Emotional Well-Being scale at baseline and one-year follow-up. Trajectories of global cognitive performance, assessed by the Modified-Mini Mental State Examination (3MS) annually up to 12 years, were estimated. All effects reported were adjusted for important confounders. Increases in PM2.5 (β = -0.144 per IQR; 95% CI = −0.261; −0.028) and NO2 (β = −0.157 per IQR; 95% CI = −0.291; −0.022) were associated with lower initial 3MS performance. Lower 3MS performance was associated with increased emotional distress (β = −0.008; 95% CI = −0.015; −0.002) over the subsequent year. Significant indirect effect of both exposures on increases in emotional distress mediated by exposure effects on worse global cognitive performance were present. No statistically significant indirect associations were found between exposures and 3MS trajectories putatively mediated by baseline emotional distress. Our study findings support cognitive aging processes as a mediator of the association between PM2.5 and NO2 exposure and emotional distress in later-life